PB2401: DETERMINING MOLECULAR BACKGROUND OF A GROUP OF CHILDHOOD LEUKEMIA/LYMPHOMA PATIENTS WITH POSITIVE FAMILY HISTORY FROM TÜRKIYE
Authors: Gizem Önder, Ufuk Amanvermez, Cengiz Canpolat, Fatih Erbey, Davut Albayrak, Elif Ince, Gul Nihal Ozdemir, Yunus Murat Akcabelen, Nese Yarali, Namik Yasar Ozbek, Ikbal Okbozkaya, Turan Bayhan, Dilek Kacar, Omer Dogru, Koray Yalcin, Nihat Bugra Agaoglu, Ozkan Ozdemir, Ugur Ozbek, Ozden Hatirnaz Ng
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background Leukemia is the disease of bone marrow, characterized by uncontrolled proliferation of immature lymphocytes and lymphoma is the cancer of the lymphatic system. Both malignancies are multifactorial and their etiology is still unclear but around 8% of all childhood cases are shown to possess hereditary features. Next generation sequencing is installed in the diagnostics of leukemias and lymphomas and targeted panel sequencing or whole exome sequencing can easily determine the underlying predispositions genes. Aims: Here we aimed to determine the possible predisposition variants in childhood leukemia/lymphoma patients with family history. The output of this study can help to explain early leukemia/lymphoma development in childhood, can direct the choice of treatment and can be used in genetic counseling for family members. Methods: In total 14 index cases and 54 family members were enrolled in the study. DNA isolation from peripheral blood/bone marrow samples were obtained from patients with leukemia or lymphoma. Depending on the pedigree information the patients were analyzed by targeted panels or WES by a service provider. The raw data were processed at Acibadem University Rare Diseases and Orphan Drugs Application and Research Center (ACURARE) by an inhouse filtering flow with four different variant calling tools. Annotation and filtering were done via GENNext (https://gennext-edge.farplane.dev/server/nocache/login.html). The list of genes related to hematological cancers, genes predisposing to hereditary cancers, and genes related to cancer predisposing syndromes are primarily analyzed. If no related variant is detected, less stringent filters are applied for variant discovery. Results: Among 14, in 11 cases a pathogenic/likely pathogenic variant was determined. All variants were validated by Sanger sequencing and also confirmed in other affected family members.The genes involved were TP53, ATR, ETV6, BMP6, DNHD1, JAK2, JAK3, MSH6, MLH1, BRCA1 and BRCA2. These results show that the germline inheritance of cancer predisposing genes can also play a role in the etiology of childhood leukemias and/or lymphomas. There were also six alterations with the classification of variant of unknown significance (VUS). Variants were also confirmed in ancillary tissues where available. Summary/Conclusion Despite comprehensive molecular analysis the genetic etiology of childhood leukemias/lymphomas is still not clear. Analyzing germline variations is important especially in childhood cases with a familial background. There are some strong VUS to confirm the phenotypic effect of the alteration and further functional studies are needed to explain the clinical relevance of these variations. Another aspect of germline testing is to provide genetic counseling to other family members for preventive or early diagnostic approaches. Keywords: Familial, Lymphoma, Acute leukemia, Childhood